The immunologic consequences of HIV infection are loss of T helper and effector cell functions and severe reduction of CD4 T cell numbers. Because circulating HIV consists mainly of viral particles that are not productively infectious (>99%), we investigated whether HIV rendered noninfections by Aldrithiol-2 treatment (AT-2 HIV) would bind CD4 plasmacytoid dendritic cells (pDC) and/or T cells resulting in selective apoptosis of CD4 T cells and loss of T helper(CD4) and effector (CD8) cell function. Our findings indicate that, upon 24-hr exposure to AT-2 HIV, pDC produce interferon-alpha (IFN-alpha) and indoleamine 2,3-dioxygenase (IDO). IFN-alpha is essential for inducing TNF-Related Apoptosis-Inducing Ligand (TRAIL) on CD4 T cells, and AT-2 HIV induces TRAIL death receptor 5 (DR5) on CD4 T cells, resulting in their apoptosis. This mechanism has been suggested to be important for eliminating HIV-infected CD4 T cells. IDO catabolizes tryptophan, resulting in functional inhibition of both CD4 CD8 T cells. The CD4 T cells are blocked at or near the G1-S transition phase of the cellcycle, whereas the CD8 T cells are blocked from entering the cell cycle. This inhibition could reduce the activated CD4 T cell target pool for HIV-1 infection. However, because the great majority of circulating HIV is noninfectious, there is a higher statistical probability that HIV-CD4 binding events will be noninfectious and will kill and disarm otherwise healthy T cells, we hypothesize that the net effect of these HIV-hijacked immune regulatory mechanisms will be immunopathogenic and advantageous for the virus. Much of our in vitro data are supported by ex vivo studies involving patient blood and lymphoid tissue.